Glaucoma refers to a group of optic neuropathies that are characterized by loss of retinal ganglion cells and atrophy of the optic nerve with resultant visual field loss. The disease is the leading cause of irreversible blindness worldwide and the second leading cause of blindness, behind cataracts. Clinical trials have demonstrated that elevated IOP is a major risk factor for glaucoma and have validated the role of lowering IOP in the management of glaucoma.
Glaucoma is classified according to three parameters: 1) the underlying cause, i.e., primary (idiopathic) or secondary (associated with some other ocular or systemic conditions); 2) the state of the anterior chamber angle, i.e., open angle (open access of the outflowing aqueous humor to trabecular meshwork) or closed angle (narrow angle; the trabecular meshwork is blocked by apposition of the peripheral iris and the cornea); and 3) chronicity, i.e., acute or chronic. Although secondary forms of glaucoma with clear etiologies do exist (e.g., pseudoexfoliation and pigmentary dispersion), the most common form of glaucoma is primary open angle glaucoma (POAG).
Occular Hypertension (OHT) is a condition in which IOP is elevated but no glaucomatous findings have been observed (Bell and Charleton, 2011-http://emedicine.medscape.com/article/1207470-overview). The Ocular Hypertension Study demonstrated that patients with OHT have an overall risk of 10% over 5 years of developing glaucoma and that this risk can be cut in half by the institution of medical treatment that reduces IOP. Latanoprost is described in, for example, U.S. Pat. Nos. 5,296,504; 5,422,368; 6,429,229 and 7,163,959, all of which are incorporated herein by reference in their entirety.
Latanoprost has been used as a topical ophthalmic medication for controlling the progression of glaucoma or ocular hypertension by reducing intraocular pressure. It is a prostaglandin analogue that works by increasing the outflow of aqueous fluid from the eyes (through the uveoscleral tract). Latanoprost, which is marketed as Xalatan™ is indicated for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension.
Applicant has been conducting clinical studies with an A1 agonist. These studies have been described in co-pending application WO 2010/127210. The Applicant has shown clinically significant reduction of intraocular pressure using an A1 agonist in human subjects having glaucoma. The specifications of WO 2010/127210 are herein incorporated in their entirety as if individually set forth.
Applicant has recently conducted pre-clinical studies and found that the use of a combination of an A1 agonist, specifically Compound A, and a prostaglandin analog, specifically latanoprost, provided significant IOP reduction in normotensive monkeys.